16-Methylene steroids are well known chemically in the estrone (aromatic A ring) series, see U.S. Pat. Nos. 3,257,429 and 3,275,666; in the corticoid series, see U.S. Pat. Nos. 3,157,679, 3,878,228, 3,354,184, 3,493,558 and 3,376,294; and in the progesterone series, see U.S. Pat. Nos. 3,168,537, 3,157,679, 3,284,476, 3,328,432 and 3,359,287. In the androstane series, see U.S. Pat. Nos. 3,641,069 and 3,300,521; Gazz, Chim. Ital. 91, 672 (1961); Hungarian Pat. No. 019,495; and U.S. patent application Ser. No. 349,490, filed Feb. 17, 1982.
Steroids with a 17.alpha.-ethynyl-17.beta.-hydroxy group are well known to those skilled in the art and are referred to as ethisterone type steroids. These propargyl alcohols are known with methyl substitution at the C-16 position. For example, U.S. Pat. No. 4,041,055 discloses various 16.alpha.-methyl and 16.beta.-methyl ethisterones but no 16-methylene ethisterones, see Examples 23, 24, 26, 29 and 43. U.S. Pat. No 3,231,702, generically discloses 16(.alpha. and .beta.)-substituted 17.alpha.(haloethynyl)-17.beta.-hydroxy steroids.
Processes to transform 17-keto steroids to the corresponding 17.alpha.-ethynyl-17.beta.-hydroxy steroid by reacting the 17-keto steroid with acetylene or acetylene salts in the presence of a base are well known to those skilled in the art, see for example U.S. Pat. Nos. 4,041,055 (Preparation 1), 3,441,559, 3,972,906, 3,759,961, 3,734,935, 3,689,512, etc.
In 17.alpha.-hydroxyprogesterones, the 17-hydroxy group is .alpha. and the acetyl group is .beta.. The unnatural or opposite configuration (17.beta.-hydroxy-17.alpha.-acetyl), as in the 17.beta.-hydroxy steroids (V), is also known, see for example Fried & Edwards Vol II, p. 135 No. 5 and Helv. Chim. Acta 26,680 (1943).
The conversion of ethisterone type steroids to 17.beta.hydroxy-17.alpha.-acetyl type steroids by use of mercury compounds is known, see M. W. Goldberg, Helv. Chim. Acta 26, 680 (1943). That paper, published almost 40 years ago, erroneously reports 17.beta.-hydroxy as 17.alpha.-hydroxy. None of the compounds in Goldberg's paper have any substitution at the C-16 position. U.S. Pat. No. 4,102,908 discloses a process for transformation of the nitrate ester of ethisterone type compounds to 17.alpha.-hydroxyprogesterones. None of the compounds exemplified in U.S. Pat. No. 4,102,908 have any substitution at the C-16 position.
Steroidal sulfoxides are known, see for example U.S. Pat. Nos. 4,041,055 and 4,342,702. In U.S. Pat. No. 4,041,055, the sulfoxide is a 20-methoxy-21-(phenylsulfinyl)-.DELTA..sup.17 (.sup.20) steroid. In U.S. Pat. No. 4,342,702, the sulfoxide is a 21-chloro-20-methoxy-21-(phenylsulfinyl)-.DELTA..sup.17 (.sup.20) steroid. The sulfoxide of the present invention, the 16-(phenylsulfinylmethyl)-.DELTA..sup.16 steroid (VI) is readily transformed to a 16-methylene-17.alpha.-hydroxyprogesterone (VII). The prior art sulfoxides of U.S. Pat. No. 4,041,055 produce 16-methyl(.alpha. and .beta.) substituted 17.alpha.-hydroxyprogesterones but not the desired 16-methylene-17.alpha.-hydroxyprogesterones of the present invention. Likewise, the prior art sulfoxides of U.S. Pat. No. 4,342,702 produce 21-halo-16-methyl(.alpha. or .beta.) substituted 17.alpha.-hydroxyprogesterones but not the desired 16-methylene-17.alpha.-hydroxyprogesterones of the present invention. This is extremely important, because even though the 16-methylene-17.alpha.-hydroxyprogesterones (VII) of the present invention can be transformed to the 16-methyl-17.alpha.-hydroxyprogesterones of U.S. Pat. No. 4,041,055 and the 21-halo-16-methyl-17.alpha.-hydroxyprogesterones of U.S. Pat. No. 4,342,702, the 16-methylene group is necessary for production of melengestrol acetate (17.alpha.-acetyloxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione), and therefore melengestrol acetate cannot be produced from the prior art sulfoxides.
U.S. Pat. No. 4,041,055 discloses a process for the transformation of an ethisterone type steroid to the corresponding sulfoxide by use of a sulfenylating agent. That reaction proceeds via an allene sulfoxide intermediate. Likewise, U.S. Pat. No. 4,342,702 transforms a halo substituted ethisterone type steroid to the corresponding 21-halo substituted sulfoxide by use of a sulfenylating agent via a 21-halo allene sulfoxide. The sulfenylation reaction of the present invention does not proceed via an allene sulfoxide intermediate.
16-Methylene-17.alpha.-hydroxyprogesterones are known. See, for example, J. Chem. Soc. 2385 (1960) and U.S. Pat. Nos. 3,040,069, 3,130,209, 3,157,679, 3,168,537, 3,284,476 and 3,359,287. In U.S. Pat. No. 3,359,287 the compound of formula (X) is the closest to the compound of formula (VIIB). Similarly the compound of formula (VI) of U.S. Pat. No. 3,359,287 is the closest compound to the 16-methylene-17.alpha.-hydroxyprogesterone (VIIC). However, U.S. Pat. No. 3,359,287 requires both substituents at C-11 to be hydrogen atoms which is significantly different from the functionalized C-11 positions in the compounds of the present invention. None of these 16-methylene-17.alpha.-hydroxyprogesterones were produced from a sulfoxide by reaction with a thiophile as in the present invention.
16-Methylene corticoids are known, see U.S. Pat. No. 3,115,508. The 16-methylene corticoids disclosed were 5.alpha. or saturated A-ring corticoids. The 16-methylene corticoids of the present invention have unsaturation in the A or B-rings.
U.S. Pat. No. 4,041,055 claims a process for transforming a 16.alpha.- or 16.beta.-methyl-17-keto steroid to the corresponding 16(.alpha. or .beta.)-methyl-17.alpha.-hydroxyprogesterone. The process involved ethynylating the 17-keto steroid to produce a 17.alpha.-ethynyl-17.beta.-hydroxy steroid which was then sulfenylated to form an allene sulfoxide. Michael addition to the allene sulfoxide produced the corresponding sulfoxide. Reaction of the sulfoxide with a thiophile produced a 17.alpha.-hydroxy-20-alkoxy-20-unsaturated steroidal side chain which upon acid hydrolysis produced the 17.alpha.-hydroxyprogesterone side chain. U.S. Pat. No. 4,041,055 discloses that if one starts with a 16.alpha.- or 16.beta.-methyl 17-keto steroid, one then following the above process produces the corresponding 16.alpha.- or 16.alpha.-methyl-17.alpha.-hydroxyprogesterone. U.S. Pat. No. 4,041,055 makes absolutely no mention of 16-methylene substitution. In addition the process and intermediates of the present invention are quite different than those of U.S. Pat. No. 4,041,055.
U.S. Pat. No. 4,342,702 discloses a process for the transformation of a 16(.alpha. or .beta.)-methyl-17-keto steroid to a 21-halo-16(.alpha. or .beta.)-methyl-17.alpha.-hydroxypregnane by converting the 17-keto starting material to a halogen substituted ethisterone type steroid by use of a halogenated acetylene. The halogen substituted ethisterone type steroid is reacted with a sulfenylating agent to form a 21-halo allene sulfoxide which is converted to the corresponding 21-halo sulfoxide and ultimately to the 21-halo-16(.alpha. or .beta.)-methyl-17.alpha.-hydroxyprogesterone.